Hexarelin

Hexarelin, also known by its International Nonproprietary Name (INN) examorelin, is a synthetic hexapeptide growth hormone secretagogue composed of six amino acids in the sequence His-D-2MeTrp-Ala-Trp-D-Phe-Lys-NH2 ⁽¹⁾. It was developed by Mediolanum Farmaceutici under the development codes EP-23905 and MF-6003 as a structural analog of GHRP-6, differing in that it adds two methyl groups to the tryptophan residue. This modification increases both binding affinity and chemical stability compared to the parent compound ^(1,5).

Hexarelin has a molecular formula of C47H58N12O6 and a molecular weight of 887.04 g/mol (CAS 140703-51-1) ⁽⁵⁾. It is orally active, centrally penetrant, and among the most potent GH-releasing agents in the GHRP class ⁽¹⁾. What truly sets Hexarelin apart from other secretagogues is not its GH potency alone, but its ability to bind a second receptor, CD36, found specifically in cardiac tissue. This cardiac-specific binding has no equivalent in GHRP-2, GHRP-6, or Ipamorelin, and it opens an entire research domain (cardiovascular biology) that is unique to Hexarelin.

Hexarelin entered Phase II clinical trials for the treatment of growth hormone deficiency and congestive heart failure, but did not complete development and was never marketed ⁽⁵⁾. It is not FDA-approved and has not been placed on the FDA’s Category 2 list. All Healius Peptides Hexarelin is sold strictly for in vitro research purposes.

Hexarelin operates through two distinct receptor systems, a characteristic that is unique among all growth hormone secretagogues.

Pathway 1: GHS-R1a (Growth Hormone Release)

Like all GHRPs, Hexarelin binds the growth hormone secretagogue receptor type 1a (GHS-R1a) on pituitary somatotrophs and hypothalamic neurons. This triggers phospholipase C activation, protein kinase C (PKC) signaling (also spelled signaling), and an increase in intracellular calcium, resulting in GH vesicle exocytosis ^(1,6). At the hypothalamic level, Hexarelin stimulates GHRH neuron activity while suppressing somatostatin, amplifying the pulsatile GH signal ⁽⁶⁾. The GH response to Hexarelin exceeds that of GHRH alone, and co-administration with GHRH produces what the literature describes as “massive” increases in plasma GH levels even at low Hexarelin doses ⁽⁵⁾.

Pathway 2: CD36 (Cardiac Protection)

The discovery that Hexarelin binds a second receptor in cardiac tissue was a landmark finding. Using radioactive photoactivatable derivatives of Hexarelin, researchers identified CD36 as the specific cardiac binding protein ⁽²⁾. CD36 is a multifunctional glycoprotein expressed in cardiomyocytes and microvascular endothelial cells. Critically, ghrelin itself does not displace Hexarelin from CD36 binding sites in non-endocrine tissues such as the heart, confirming that CD36 is a Hexarelin-specific receptor distinct from GHS-R1a ^(2,5). Activation of CD36 by Hexarelin triggers pro-survival signaling cascades, including activation of the PI3K/Akt pathway, enhanced Bcl-2 expression (anti-apoptotic), and reduced caspase-3 activity (pro-apoptotic) ^(2,3). These cardioprotective effects occur independently of growth hormone release.

Secondary Hormonal Effects

Unlike Ipamorelin, which is fully GH-selective, Hexarelin does elevate prolactin, ACTH, and cortisol at GH-releasing doses ^(1,7). These elevations are dose-dependent and generally transient. Hexarelin does not affect plasma glucose, LH, FSH, or TSH levels ⁽⁵⁾. The cortisol and prolactin profiles are comparable to those of GHRP-2 and GHRP-6.

Cardioprotection and Ischemia-Reperfusion Injury

This is the research domain where Hexarelin has no peers. In myocardial ischemia-reperfusion (I/R) injury models, Hexarelin treatment reduced infarct size by approximately 50% in wild-type mice. This effect was completely abolished in CD36 knockout animals, confirming the receptor’s essential role ^(2,3). A 2017 study by Huang et al. showed that Hexarelin improved cardiac systolic function, decreased malondialdehyde production (an oxidative stress marker), and increased the number of surviving cardiomyocytes after I/R injury. These protective effects were mediated through modification of the IL-1 signaling pathway via cardiac GHS-R1a receptors ⁽³⁾. Hexarelin was more potent than equimolar ghrelin in preventing increases in LV end-diastolic pressure and creatine kinase release in perfused hearts from hypophysectomized rats ^(2,4).

Anti-Atherosclerotic Activity

In adult Sprague-Dawley rats, Hexarelin treatment suppressed atherosclerotic plaque formation and neointima development, partially reversed the HDL/LDL cholesterol ratio, and increased serum nitric oxide levels ⁽⁴⁾. Hexarelin also decreased vascular smooth muscle cell proliferation, calcium sedimentation in the aortic wall, and foam cell formation induced by oxidized LDL ⁽⁴⁾. These anti-atherosclerotic effects are characterized (also spelled characterized) as GH-independent, occurring through activation of cardiac receptors rather than systemic GH elevation.

Growth Hormone Release

Hexarelin is among the most potent GH releasers in the GHRP family. In clinical studies, Hexarelin released more GH than GHRH alone in human subjects, and the combination of Hexarelin with GHRH produced synergistic GH amplification ^(5,7). The GH-releasing efficacy of Hexarelin exceeds that of GHRP-6 at matched doses and is comparable to GHRP-2⁽⁷⁾. Unlike some secretagogues, short-term intranasal Hexarelin administration did not produce desensitization of the GH response in aging (also spelled aging) human subjects ⁽⁸⁾.

Lipid Metabolism

Hexarelin has demonstrated improvements in lipid metabolic profiles in non-obese insulin-resistant mouse models, reducing adiposity and improving markers of lipid handling independently of its GH-releasing activity ⁽⁹⁾. Chronic treatment in obese rats significantly decreased plasma cholesterol concentrations ⁽⁴⁾. These metabolic effects, mediated at least in part through CD36, add another dimension to Hexarelin’s research profile beyond GH and cardiac applications.

Healius Peptides supplies Hexarelin as a 5mg lyophilized powder in a sealed, sterile vial. Reconstitution requires bacteriostatic water (BAC water).

Reconstitution

Draw the desired volume of BAC water into a sterile syringe. Insert the needle through the vial stopper and direct the stream slowly down the inside wall of the vial. Do not aim directly at the lyophilized pellet. Allow the powder to dissolve naturally; gently swirl if needed, but do not shake. The resulting solution should be clear before use. Use our Hexarelin dosage calculator to determine the correct reconstitution volume for your target concentration.

Research Dosage Ranges

In published clinical and preclinical protocols, Hexarelin doses typically range from 1 to 2 micrograms per kilogram of body weight, administered intravenously or subcutaneously ^(1,7). Common research doses range from 100 to 300 micrograms per administration. The Arvat et al. study used 1 and 2 mcg/kg IV doses in healthy young adults, with both dose levels producing strong GH responses exceeding those of GHRH ⁽⁷⁾. Cardiac research protocols in animal models have used 80 to 100 mcg/kg per day, typically administered twice daily ^(3,4).

Storage

Store unreconstituted Hexarelin at -20°C for long-term stability. Once reconstituted with BAC water, store the vial at 2 to 8°C and use within 14 to 21 days. Avoid repeated freeze-thaw cycles. Protect from direct light.

Hexarelin shares the broader hormonal profile common to most GHRPs (excluding Ipamorelin). Researchers should be aware of the following dose-dependent effects documented in clinical and preclinical literature.

Cortisol and ACTH Elevation

The head-to-head comparison by Arvat et al. of Hexarelin and GHRP-2 found that both peptides stimulated ACTH and cortisol secretion at levels comparable to those of human corticotropin-releasing hormone (hCRH) ⁽⁷⁾. These elevations are transient, typically returning to baseline within 2 to 3 hours. The cortisol response is dose-dependent, becoming more pronounced at higher doses.

Prolactin Elevation

Hexarelin produces a mild, dose-dependent increase in prolactin. In the Arvat et al. study, the prolactin response to Hexarelin was significantly lower (p < 0.01) than that produced by TRH ⁽⁷⁾. At standard research doses, prolactin elevations are modest and comparable to those seen with GHRP-2 and GHRP-6.

Desensitization Considerations

Some data suggest that prolonged continuous Hexarelin use may lead to partial attenuation of the GH response over time. However, a study by Ghigo et al. found that short-term intranasal Hexarelin did not desensitize the GH response in elderly subjects ⁽⁸⁾. Researchers running extended protocols should consider cycling (4 to 8 weeks on, equivalent rest period) to minimize (also spelled minimize) any potential for receptor downregulation.

What Hexarelin Does Not Affect

Hexarelin does not alter plasma glucose, LH, FSH, or TSH levels at any dose tested ⁽⁵⁾. This means that while it is not as hormonally clean as Ipamorelin (which avoids cortisol and prolactin entirely), it is still selective enough to leave glucose metabolism and reproductive hormones unaffected.

Hexarelin and Ipamorelin both act on the ghrelin receptor (GHS-R1a), but they represent opposite ends of the GHRP spectrum: Hexarelin maximizes potency and breadth of action, while Ipamorelin maximizes selectivity.

GH Potency

Hexarelin is the more potent GH releaser. Head-to-head data in swine showed GHRP-2 at the top for potency (ED50 = 0.6 nmol/kg), followed by Ipamorelin (ED50 = 2.3 nmol/kg) and GHRP-6 (ED50 = 3.9 nmol/kg), with Hexarelin producing GH responses exceeding GHRP-6 and approaching GHRP-2 levels ^(1,7). For protocols prioritizing maximum GH output, Hexarelin outperforms Ipamorelin.

Selectivity

Ipamorelin wins this comparison decisively. It produces no elevation of cortisol, ACTH, or prolactin, even at doses 200-fold above its GH-releasing ED50 ⁽¹⁾. Hexarelin elevates all three at GH-effective doses ⁽⁷⁾. For protocols where hormonal purity matters and cortisol or prolactin are confounding variables, Ipamorelin is the only GHRP that delivers a clean signal.

Cardiac Research

This is where the comparison becomes one-sided in Hexarelin’s favor (also spelled favor). Hexarelin binds CD36 in cardiac tissue, triggering cardioprotective signaling that is entirely independent of GH release ^(2,3). Ipamorelin does not bind CD36 and has no published cardiac-specific research applications. Any protocol involving cardiac ischemia, reperfusion injury, atherosclerosis, or post-MI remodeling (also spelled remodeling) models requires Hexarelin.

Appetite

Neither compound produces strong appetite stimulation. Hexarelin may cause mild orexigenic effects through its ghrelin receptor activity, but these are substantially less pronounced than GHRP-6. Ipamorelin causes no stimulation of appetite at all ⁽¹⁾.

1. Raun K, Hansen BS, Johansen NL, et al. Ipamorelin is the first selective growth hormone secretagogue. European Journal of Endocrinology. 1998;139(5):552-561. Head-to-head comparison of GHRPs in swine: Hexarelin GH potency exceeding GHRP-6. GHRP-2 and Hexarelin both elevate ACTH and cortisol; Ipamorelin does not. Benchmark selectivity data for the GHRP family.

2. Bhatt DK, et al. CD36 mediates the cardiovascular action of growth hormone-releasing peptides in the heart. Journal of Biological Chemistry. 2002;277(20):17878-17885. Identification of CD36 as a specific cardiac receptor for Hexarelin. Expressed in cardiomyocytes and microvascular endothelial cells. Ghrelin does not displace Hexarelin from CD36 in non-endocrine tissues. CD36 activation increases coronary perfusion pressure in a dose-dependent manner. Effect abolished in CD36-null mice.

3. Huang J, Li Y, Zhang J, Liu Y, Lu Q. The growth hormone secretagogue Hexarelin protects rat cardiomyocytes from in vivo ischemia/reperfusion injury through interleukin-1 signaling pathway. International Heart Journal. 2017;58(2):257-263. Hexarelin improved cardiac systolic function, decreased malondialdehyde levels, and increased the number of surviving cardiomyocytes. IL-1beta downregulation and IL-1Ra upregulation via GHSR1a activation. Effects neutralized by GHSR antagonist.

4. Pang J, Xu Q, Xu X, et al. Hexarelin suppresses high-lipid diet- and vitamin D3-induced atherosclerosis in the rat. Peptides. 2010;31(4):630-638. Suppressed atherosclerotic plaque formation and neointima—partially reversed HDL/LDL ratio. Increased serum nitric oxide and aortic eNOS mRNA. Decreased vascular smooth muscle proliferation, calcium sedimentation, and foam cell formation. Decreased plasma cholesterol in obese rats.

5. Examorelin (Hexarelin) pharmacological profile. Wikipedia / PubChem CID 6918297. Developed by Mediolanum Farmaceutici (EP-23905, MF-6003). Hexapeptide His-D-2MeTrp-Ala-Trp-D-Phe-Lys-NH2, MW 887.04, CAS 140703-51-1. Phase II trials for GH deficiency and congestive heart failure (not completed). Orally active. Synergistic with GHRH, producing massive GH elevations. Does not affect glucose, LH, FSH, or TSH.

6. Torsello A, Grilli R, Luoni M, et al. Mechanism of action of Hexarelin. I. Growth hormone-releasing activity in the rat. European Journal of Endocrinology. 1996;135(4):481-488. GH-releasing mechanism via the PKC signaling pathway in pituitary somatotrophs. Hypothalamic GHRH stimulation and somatostatin suppression.

7. Arvat E, Di Vito L, Maccagno B, et al. Effects of GHRP-2 and Hexarelin, two synthetic GH-releasing peptides, on GH, prolactin, ACTH, and cortisol levels in man. Peptides. 1997;18(6):885-891. GHRP-2 and Hexarelin produced similar dose-dependent GH responses exceeding GHRH (P < 0.05). PRL response lower than TRH (P < 0.01). ACTH/cortisol is comparable to hCRH—age-dependent decline in older people —but still exceeds GHRH.

8. Ghigo E, Arvat E, Gianotti L, et al. Short-term administration of intranasal or oral Hexarelin, a synthetic hexapeptide, does not desensitize the growth hormone responsiveness in human aging. European Journal of Endocrinology. 1996;135(4):407-412. Short-term intranasal Hexarelin did not attenuate the GH response in elderly subjects.

9. Mosa R, Huang L, Wu Y, et al. Hexarelin, a growth hormone secretagogue, improves lipid metabolic aberrations in nonobese insulin-resistant male MKR mice. Endocrinology. 2017;158(10):3174-3187. Improved lipid metabolism, reduced adiposity, and improved markers of lipid handling independently of GH-releasing activity in insulin-resistant mouse models.

10. Marleau S, Mulumba M, Lamontagne D, et al. Cardiac and peripheral actions of growth hormone and its releasing peptides: relevance for the treatment of cardiomyopathies. Cardiovascular Research. 2006;69(1):26-35. Review of Hexarelin cardiac actions. Hexarelin is more potent than equimolar ghrelin for cardiac protection. GH-independent cardiovascular effects through CD36 and GHSR activation.

This product is intended for laboratory research use only. It is not a drug, food, cosmetic, or dietary supplement, and it is not intended for human or veterinary consumption. Hexarelin (examorelin) has not been approved by the U.S. Food and Drug Administration for any therapeutic indication. All information provided in this document is drawn from published, peer-reviewed scientific literature and is intended solely to support researchers in designing and interpreting in vitro studies. Healius Peptides makes no claims regarding the safety, efficacy, or suitability of this product for any use other than laboratory research. Buyers accept full responsibility for ensuring their use complies with all applicable local, state, federal, and international regulations.